Large amounts of TNF-α are quickly released by stimulated mast cells. All the cells involved in inflammation have receptors for TNF-α and are activated by it to synthesize more on their own. This positive feedback quickly amplifies the response.

The granules of mast cells are loaded with histamine and their exocytosis releases this potent mediator. Histamine increases the blood flow to the area and the leakage of fluid and proteins from the blood into the tissue space. Thus the quick release of histamine produces the redness and swelling associated with inflammation.

Inflammasomes

IL-1 is synthesized from a larger precursor that is cleaved by a caspase (caspase-1). Caspase-1 is part of a multi-protein complex in the cytosol of macrophages and neutrophils called an inflammasome. Inflammasomes are activated by several different products produced by invading bacteria. Some of these are first "seen" by toll-like receptors (TLRs) thus providing a link between the innate immune system and inflammation.

In chronic inflammation, the inflammatory response is out of proportion to the threat it is faced with or is directed against inappropriate targets. In the first case, the result can be more damage to the body than the agent itself would have produced.

The NSAIDs achieve their effects by blocking the activity of cyclooxygenases.

The body produces two different forms of cyclooxygenase:

COX-1, which is involved in pain, promoting clotting, and protecting the stomach;

COX-2, which is involved in the pain produced by inflammation.

In addition to reducing the fever and pain of inflammation, NSAIDs also inhibit clotting. They do this by interfering with the synthesis of thromboxane A2 in platelets. This is the reason that

aspirin is given to patients undergoing angioplasty;

many people take a baby aspirin a day in the hope of avoiding heart attacks.

But regular use of NSAIDs has a downside: a tendency to develop ulcers in the stomach and duodenum.

Most of the NSAIDs inhibit both COX-1 and COX-2. However, some newer drugs, the so-called COX-2 inhibitors, such as

rofecoxib (Vioxx®)

celecoxib (Celebrex®)

are much more active against COX-2 than COX-1.

COX-2 inhibitors are effective against inflammation and avoid damage to the GI tract. But, unfortunately, they increase the risk of blood clots — which can cause heart attacks and strokes — because they do not block the synthesis of thromboxane A2 by platelets (which contain only COX-1). So people depending on NSAIDs for their heart protective effects must monitor any use of COX-2 inhibitors carefully.

In fact, because of the increased risk of heart attacks and strokes, the manufacturer of Vioxx® removed it from the market on 30 September 2004.

etanercept (Embrel®). A soluble version of the TNF-α receptor. It binds TNF-α preventing it from carrying out its many inflammatory actions. Potent but carries a severe risk of allowing infections to develop.

recombinant protein C. To help the body dissolve the tiny clots that are triggered during inflammation.

On occasions, for reasons that are not entirely clear, the inflammatory response — usually to an infection by lipopolysaccharide (LPS)-bearing Gram-negative bacteria — spirals out of control progressing until it involves the entire body. This life-threatening development is called sepsis.

The circulatory system loses its integrity:

There is a breakdown of the adherens junctions between the cells lining the capillaries allowing fluid to leak into the tissue spaces — edema.

There is a breakdown in the control of blood clotting. What should have been a mechanism to help wall off an infected area and promote healing leads instead to a dangerous deposition of fibrin in small blood vessels throughout the body.

Some Gram-positive cocci can produce a similar condition, but here the eliciting agent is not LPS but a toxin liberated by the bacteria.

In theory, anti-inflammatory agents should be useful in combating sepsis. But so far, only recombinant protein C has shown any promise (by inhibiting the formation of thrombin), and severe bleeding is a dangerous side-effect.

Chronic infection with the liver flukeOpisthorchis viverrini is responsible for many cases of bile duct cancer in Thailand and Laos.

Bladder, colon, pancreas, stomach, and other cancers may similarly be the final stage of years of inflammation.

The strong link between chronic inflammation and cancer should not be surprising when you consider that

the reactive oxygen species (ROS) liberated during inflammation are powerful DNA-damaging agents [Link];

increased mitosis in response to inflammation puts more cells at risk of mutations as they replicate their DNA during S phase;

Apoptosis, the programmed death of damaged cells, is suppressed in inflamed tissue. So cells with precancerous genetic mutations, which should have committed suicide, live on to grow into a full-blown cancer.